CS195905B1 - 6-substituted derivatives of d-8-ergolin-i-ylacetic acid amide and process for preparing thereof - Google Patents
6-substituted derivatives of d-8-ergolin-i-ylacetic acid amide and process for preparing thereof Download PDFInfo
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- CS195905B1 CS195905B1 CS767932A CS793276A CS195905B1 CS 195905 B1 CS195905 B1 CS 195905B1 CS 767932 A CS767932 A CS 767932A CS 793276 A CS793276 A CS 793276A CS 195905 B1 CS195905 B1 CS 195905B1
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- formula
- ergolin
- ylacetamide
- hydrazides
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- 150000001408 amides Chemical class 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 8
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 235000005985 organic acids Nutrition 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 230000000085 anti-nidation effect Effects 0.000 abstract 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- QTWZVXVIOJJQTN-WQRMPROISA-N 2-[(6ar,9s,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]acetamide;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC([C@H]2C[C@@H](CC(N)=O)CN([C@@H]2C2)C)=C3C2=CNC3=C1 QTWZVXVIOJJQTN-WQRMPROISA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000004451 Pituitary Gonadotropins Human genes 0.000 description 1
- 108010081865 Pituitary Gonadotropins Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Vynález se týká 6-substituovaných derivátů amidu kyseliny D-8-ergolin-I-yloctové obecného vzorce IThe invention relates to 6-substituted D-8-ergolin-1-ylacetic acid amide derivatives of the general formula I
CH.CONH /<, i 1CH.CONH /
ve kterém R značí alkyl se 2 až 4 atomy uhlíku, allyl, cykloalkyl s 5 až 6 atomy uhlíku a dialkylaminoethyl, ve kterém alkyl má 1 až 3 atomy uhlíku, jejich farmaceuticky vhodných solí s anorganickými i organickými kyselinami, jakož i způsobů výroby uvedených látek.wherein R is C 2 -C 4 alkyl, allyl, C 5 -C 6 cycloalkyl, and C 1 -C 3 dialkylaminoethyl, pharmaceutically acceptable salts thereof with inorganic and organic acids, and processes for the preparation of said compounds .
Látky obecného vzorce I a jejich soli vykázaly při biologickém hodnocení velmi výrazný inihibiční účinek na sekreci adenohypofyzárního· prolaktinu u pokusných zvířat (krysy Wistar), což se v konečném efektu projevilo^ například účinkem antilaktačním a antinidačním. Tyto účinky se projevují již po tak malých perorálně podávaných dávkách, že lze látky obecného. vzorce I ozna čit za dosud nejúčinnější inhibitory sekrece adenohypofyzárního prolaktinu.The compounds of formula (I) and their salts showed a very pronounced inhibitory effect on adenohypophysial prolactin secretion in experimental animals (Wistar rats), which in the end resulted, for example, in the anti-lactation and antinidative effects. These effects are manifested even after such small oral doses that substances of general interest can be used. of formula (I) as the most potent inhibitors of adenohypophyseal prolactin secretion.
Antinidační účinek se výrazně projevuje již při jednorázové dávce 30 ^g/kg, resp. 6 jug/kg D-6-ethyl-, resp. D-6-n-propyl-8-ergolin-I-ylacetamidu, podané orálně ve formě vodného roztoku vínanu báze, 5. den po · kopulaci. U všech pokusných zvířat došlo k zábraně březosti. V tomto směru převyšují jmenované sloučeniny účinek významně antinidačně účinného D-6-methyl-8-ergolin-I-ylacetamidu (Deprenon ^p) ) (americký pat. spis č. 3 966 941) přibližně 10 x, resp. 60x. Obdobně antilaktační účinek D-6-ethyl-, resp. D-6-n-propyl-8-ergO'lm-lIylacetamidu, stanovený z váhových přírůstků mláďat kojících krys, vyjádřený účinnou dávkou 10 .^g/ /kg/den '(hodnota EDso), podanou orálně kojícím krysám, je přibližně 20 x vyšší než u .zmíněného Deprenonu. Metoda hodnocení antinidačního ' a antilaktačního účinku byla již dříve popsána (A. Černý se sp., Collection Czechoslov. Chem. Commun. 41, 1042, 1976; M. Aušková se sp., Arzneim.-Forsch. 23, 617, 1973).The antinidative effect is already pronounced already at a single dose of 30 µg / kg, respectively. 6 [mu] g / kg D-6-ethyl-, respectively. D-6-n-propyl-8-ergolin-1-ylacetamide, administered orally as an aqueous tartrate solution, on day 5 after coupling. All experimental animals were prevented from pregnancy. In this regard, said compounds exceed the effect of the significantly antinidative D-6-methyl-8-ergolin-1-ylacetamide (Deprenone ®) (US Pat. No. 3,966,941) by approximately 10-fold and 3-fold, respectively. 60x. Similarly, the anti-lactation effect of D-6-ethyl- and resp. The D-6-n-propyl-8-ergol-1-yl acetamide, determined from the weight gain of the nursing rats, expressed as an effective dose of 10 µg / kg / day (ED 50 value) administered orally to nursing rats is approximately 20 x higher than that of Deprenon. A method for assessing the antinidative and antilactic effect has been previously described (A. Cerny et al., Collection Czechoslov. Chem. Commun. 41, 1042, 1976; M. Aušková et al., Arzneim.-Forsch. 23, 617, 1973) .
Látky obecného vzorce I jsou v poměru k účinné dávce prakticky netoxické. Například amid kyseliny D-6-ethyl-8-ergolin-I-yloctové vykazuje akutní LDso u myší při i. v.The compounds of formula I are practically non-toxic relative to the effective dose. For example, D-6-ethyl-8-ergolin-1-ylacetic acid amide shows an acute LD 50 in mice at i.v.
aplikaci 38,5 mg/kg (látka byla aplikována ve formě roztoku vínanu báze v 0,9%ním vodném roztoku chloridu ' sodného).administration of 38.5 mg / kg (the substance was applied as a solution of the tartrate base in 0.9% aqueous sodium chloride solution).
Látky obecného vzorce I rovněž 'výrazně zvyšují sekreci hypofyzárních gonadotropinů. Metodou jednostranné ovariektomie u krys (B. Benson se sp., Endocrinology 84, 369, 1969] bylo nalezeno, že 6-ethyl- a 6-n-propylanalog Deprenonu vyvolají stejné zvýšení sekrece gonadotropinů asi jako 20x vyšší dávky Deprenonu.The compounds of formula I also significantly increase the secretion of pituitary gonadotropins. By the method of unilateral ovariectomy in rats (B. Benson et al., Endocrinology 84, 369, 1969), 6-ethyl- and 6-n-propylanalog of Deprenon were found to produce the same increase in gonadotropin secretion as about 20-fold higher doses of Deprenon.
Podle vynálezu se látky obecného vzorce I připravují tak, že se nitrily obecného vzorce IIAccording to the invention, the compounds of the formula I are prepared by nitriles of the formula II
ve kterém R značí totéž co ve vzorci I, hydrolyzují na kyseliny obecného vzorce III l· CH.COGHwherein R is the same as in Formula I, hydrolyzes to acids of Formula III with CHCOGH
í Ií I
HN—ve kterém R značí totéž co· ve vzorci I, které se převádějí na odpovídající estery obecného vzorce IVHN - in which R denotes the same as in formula I, which are converted into the corresponding esters of formula IV
ve kterém R značí totéž co ve vzorci I a Ri methyl- nebo ethylskupinu, ty potom re. akcí s hydrazinem na odpovídající hydrazidy obecného· vzorce Vin which R is the same as in formula I and R 1 is methyl or ethyl, these then re. actions with hydrazine to the corresponding hydrazides of formula V
ve kterém R značí totéž co ve vzorci I, takto získané hydrazidy se převádějí v azidy, jež reakcí s amoniakem poskytnou deriváty obecného vzorce I, které se popřípadě neutralizací anorganickými nebo organickými kyselinami převádějí ve formaceuticky vhodné soli.in which R is the same as in formula I, the hydrazides thus obtained are converted into azides which, by reaction with ammonia, give derivatives of the formula I, which are optionally converted into pharmaceutically acceptable salts by neutralization with inorganic or organic acids.
Hydrolýza nitrilů obecného vzorce II na odpovídající kyseliny obecného vzorce III se účelně provádí vodněmethanolickým nebo vodněethanolickým roztokem hydroxidu draselného, při teplotě · bodu varu reakční směsi. Následující esterifikaci získaných kyselin obecného vzorce III lze . výhodně uskutečnit působením methanolického nebo ethanolického roztoku chlorovodíku, rovněž při teplotě bodu varu reakční směsi.The hydrolysis of the nitriles of the formula II to the corresponding acids of the formula III is conveniently carried out with an aqueous methanolic or aqueous ethanolic potassium hydroxide solution at the boiling point of the reaction mixture. Subsequent esterification of the acids of formula III obtained can be carried out. preferably by treatment with a methanolic or ethanolic hydrogen chloride solution, also at the boiling point of the reaction mixture.
Hydrazidy obecného vzorce V se připravují z esterů obecného vzorce IV reakcí s hydrazinhydrátem, například v koncentraci 85% hmot., při teplotě bodu varu reakční směsi, v atmosféře neoxidujícího plynu, s výhodou dusíku.Hydrazides of formula V are prepared from esters of formula IV by reaction with hydrazine hydrate, for example at a concentration of 85% by weight, at the boiling point of the reaction mixture, in an atmosphere of a non-oxidizing gas, preferably nitrogen.
Další možností · přípravy látek obecného vzorce I je ta, že se hydrazidy obecného vzorce V redukčně štěpí, s výhodou v přítomnosti Raneyova niklu, v prostředí ethanolu, při teplotě bodu varu reakční směsi, a to přímo na · deriváty obecného vzorce I.Another possibility for the preparation of the compounds of the formula I is that the hydrazides of the formula V are reductively cleaved, preferably in the presence of Raney nickel, in ethanol, at the boiling point of the reaction mixture, directly to the derivatives of the formula I.
Látky obecného vzorce I lze rovněž získávat dalšími metodami přípravy amidů, například z chloridů kyselin obecného vzorce III, popřípadě i z jiných reaktivních derivátů, například anhydridů nebo smíšených anhydridů, nebo metodami běžnými v syntéze peptidů, například s použitím N,N‘-dicyklohexylkarbodiimidu nebo karbonyldiimidažolu. Žádný z těchto· postupů však svou výtěžností a čistotou konečných produktů nedosahuje úrovně uvedených způsobů podle vynálezu.The compounds of formula (I) may also be obtained by other methods for the preparation of amides, for example from the acid chlorides of formula (III) or from other reactive derivatives, for example anhydrides or mixed anhydrides, or by conventional methods of peptide synthesis, for example using N, N'-dicyclohexylcarbodiimide or carbonyldiimidazole . However, none of these processes, by their yield and purity of the end products, reaches the level of said processes according to the invention.
Farmaceuticky vhodné soli derivátů obecného vzorce I se připravují působením nejméně 1 molekvivalentu netoxické anorganické nebo· organické kyseliny na 1 molekvivalent báze derivátu obecného vzorce I, v prostředí vhodného netečného rozpouštědla, například v methanolu, ethanolu, ve vodě nebo ve směsích těchto rozpouštědel.The pharmaceutically acceptable salts of the derivatives of formula (I) are prepared by treating at least 1 mole equivalent of a nontoxic inorganic or organic acid with 1 mole equivalent of the base of the compound of formula (I) in a suitable inert solvent such as methanol, ethanol, water or mixtures thereof.
Z kyselin použitelných pro přípravu farmaceuticky vhodných solí látek obecného vzorce I lze použít například kyseliny sírové, /Snaftalensulfonové, maleinové, vinné, jantarové a dalších. Z farmaceuticky vhodných solí látek obecného vzorce I jsou zvláště výhodné normální vínany, kyselé maleinany a adiční sloučeniny s kyselinami (^-r^^^aft^l^ensulit^novou, které jsou ve vodě dostatečně rozpustné a vhodné _ k provádění farmakologických testů nebo· k přípravě aplikačních forem.Among the acids useful for the preparation of pharmaceutically acceptable salts of the compounds of formula (I), for example, sulfuric acid, [iota] phthalene sulfonic acid, maleic acid, tartaric acid, succinic acid and others can be used. Of the pharmaceutically acceptable salts of the compounds of formula (I), particularly preferred are the normal tartrates, acid maleate and acid addition compounds (.alpha.) -, which are sufficiently water soluble and suitable for carrying out pharmacological tests; or · To prepare dosage forms.
Bližší podrobnosti způsobů výroby podle vynálezu vyplývají z následujícího příkladu provedení.Further details of the production methods according to the invention can be seen from the following exemplary embodiment.
Příklad provedeníExemplary embodiment
Methylester kyseliny D-6-ethyl-8-ergolin-I-yloctovéD-6-ethyl-8-ergolin-1-ylacetic acid methyl ester
Směs 6,0 g [0,0215 molu) D-6-ethyl-8-kyanmethylergolinu-I, 21,5 g hydroxidu draselného (0,384 molu), 95 ml ethanolu a 25 ml vody se refluxuje v atmosféře dusíku 24 hod. Po- 20 hod. stání při teplotě 5 °C se vyloučená draselná sůl kyseliny D-6-ethyl-8-engolin-I-yloctové odsaje, promyje ethanolem a po vysušení suspenduje ve 265 ml methanolu obsahujícího 6 g chlorovodíku. Směs se refluxuje 2 hod., odpaří ve vakuu do sucha a odparek se rozmíchá v 1000 ml vody. Po alkalizaci směsi nasyceným vodným roztokem uhličitanu sodného se takto získaný produkt odsaje, promyje vodou, vysuší při 50 °C a čistí chromatografií na sloupci silikagelu v soustavě chloroform + 1 '% ethanolu a dočistí krystalizací ze směsi chloroform-n-hexan (2 : 1), t. t. 178 až 179 °C, [«Id20 = 91,8° (c = 0,34, pyridin).A mixture of 6.0 g [0.0215 mol) of D-6-ethyl-8-cyanomethylergoline-I, 21.5 g of potassium hydroxide (0.384 mol), 95 ml of ethanol and 25 ml of water is refluxed under a nitrogen atmosphere for 24 hours. After standing at 5 DEG C. for 20 hours, the precipitated potassium salt of D-6-ethyl-8-engolin-1-ylacetic acid is filtered off with suction, washed with ethanol and, after drying, suspended in 265 ml of methanol containing 6 g of hydrogen chloride. The mixture is refluxed for 2 hours, evaporated to dryness in vacuo and the residue is stirred in 1000 ml of water. After alkalization with saturated aqueous sodium carbonate, the product thus obtained is filtered off with suction, washed with water, dried at 50 DEG C. and purified by chromatography on a silica gel column with chloroform + 1% ethanol and purified by crystallization from chloroform-n-hexane (2: 1). mp 178-179 ° C, [α] D 20 = 91.8 ° (c = 0.34, pyridine).
Hydrazid kyseliny D-6-ethyl-8-ergclin-I-yloctovéD-6-ethyl-8-erginolin-1-ylacetic acid hydrazide
Směs 2,6 g (0,083 molu) methylesteru D-6-ethyl-8-ergolin-I-yloctové kyseliny a 52 ml 85% ní ho hydrazinhy drátu *se refluxuje v v atmosféře dusíku 2,5 hod. Po 20 hod. stání při teplotě 5 °C se vyloučený hydrazid odsaje, promyje vodou a po vysušení čistí krystalizací ze směsi benzen-methanol (1:1), t. t. 23'8 až 241 QC, [a] o20 = —91,1° (c = 0,35, pyridin).A mixture of 2.6 g (0.083 moles) of D-6-ethyl-8-ergolin-1-ylacetic acid methyl ester and 52 ml of 85% hydrazine wire * is refluxed under a nitrogen atmosphere for 2.5 hours. After standing for 20 hours at room temperature at 5 DEG C., the precipitated hydrazide sucked off, washed with water, dried and purified by crystallization from a mixture of benzene-methanol (1: 1), mp 23'8 to 241 Q C, [a] 20 = -91.1 ° (c = 0.35, pyridine).
Amid kyseliny D-6-etlhyl-8-ergolin-I-yloctovéAn amide of D-6-ethyl-et l 8-ergoline-I-ylacetic
а) К roztoku 2,0 g (0,064 tnolu) hydrazidu kyseliny D-6-ethyl-8-ergolin-I-yloctové v 70 ml 0,2 N kyseliny chlorovodíkové se za míchání a chlazení na 0 °C přikape 5,74 ml 1 N roztoku dusitanu sodného. Po 10 min. stání při 0 QC se směs zředí 20 ml 0,2 N kyseliny chlorovodíkové, vyloučený hydrochlorid azidu kyseliny D-6-ethyl-8-ergolin-I-yloctové se odsaje, promyje 0,2 N kyselinou chlorovodíkovou a po vysušení rozmíchá v nadbytku koncentrovaného vodnéhoа) To a solution of 2.0 g (0.064 mmol) of D-6-ethyl-8-ergolin-1-ylacetic acid hydrazide in 70 ml of 0.2 N hydrochloric acid, add 5.74 ml with stirring and cooling to 0 ° C. 1 N sodium nitrite solution. After 10 min. Q stand at 0 C the mixture was diluted with 20 ml of 0.2 N hydrochloric acid, the precipitated hydrochloride acid azide D-6-ethyl-8-ergoline-I-ylacetic acid is filtered, washed with 0.2 N hydrochloric acid, dried and suspended in an excess concentrated aqueous
6' roztoku amoniaku. Po 20 hod. stání za teploty místnosti se vyloučený amid kyseliny D-6-ethyI-8-ergolin-I-yloctové přečistí krystalizací ze směsi methanol-benzen (1:1), t. t. 263 až 265 °C, [a]D 20 = —86,2 (c = 0,23, pyridin).6 'ammonia solution. After 20 hrs. Standing at room temperature, the precipitated acid amide of D-6-ethyl-8-ergoline-I-ylacetic purified by crystallization from methanol-benzene (1: 1), mp 263-265 ° C, [a] D 20 = -86.2 (c = 0.23, pyridine).
b) Směs 2,0 g (0,064 molu) hydrazidu kyseliny D-6-ethyl-8-ergolin-I-yloctové a 20 ml suspenze Raneyova niklu v 800 ml absolutního ethanolu se refluxuje 1 hod., reakční směs se zbaví katalyzátoru filtrací a filtrát se odpaří ve vakuu do sucha. Získaný amid kyseliny D-6-ethyl-8-ergolin-I-yloctové se přečistí krystalizací ze směsi methanol-benzen (1:1). Fyzikální konstanty jsou stejné jako u produktu připraveného podle a).b) A mixture of 2.0 g (0.064 mol) of D-6-ethyl-8-ergolin-1-ylacetic acid hydrazide and 20 ml of a suspension of Raney nickel in 800 ml of absolute ethanol is refluxed for 1 hour. the filtrate was evaporated to dryness in vacuo. The obtained D-6-ethyl-8-ergolin-1-ylacetic acid amide was purified by crystallization from methanol-benzene (1: 1). The physical constants are the same as for the product prepared according to a).
Kyselý maleinan amidu kyseliny D-6-ethyl-8-ergolin-I-yloctové se připraví z 1 molekvivalentu báze a 1,1 molekvivalentu kyseliny maleinové v methanolu; t. t. 112 až 115 °C, [a:]D 20 = —41,5° (c = 0,24, methanol).D-6-ethyl-8-ergolin-1-ylacetic acid amide maleic acid was prepared from 1 mole equivalent of base and 1.1 mole equivalent of maleic acid in methanol; mp 112-115 ° C, [α] D 20 = -41.5 ° (c = 0.24, methanol).
Sůl s kyselinou /?-naftalensulfonovou se připraví z 1 molekvivalentu báze a 1,1 molekvivalentu kyseliny ^-naftalensulfonové v ethanolu, t. t. 234 až 238 °C, [a]D 20 = —34,7° (c = 0,1, methanol).The? -Naphthalenesulfonic acid salt is prepared from 1 mole equivalent of base and 1.1 mole equivalent of? -Naphthalenesulfonic acid in ethanol, mp 234-238 ° C, [α] D 20 = -34.7 ° (c = 0.1, methanol).
Kyselý vínan se připraví z 1 molekvivalentu báze a 1,1 molekvivalentu kyseliny vinné v ethanolu, t. t. 232 až 235 °C, [a]D20 = -35,2° (c = 0,19, methanol).Bitartrate Prepared from 1 mole equivalent of base and tartaric acid 1.1 molar equivalents in ethanol, mp 232-235 ° C, [a] D 20 = -35.2 ° (c = 0.19, methanol).
Normální vínan se připraví ze 2 molekvivalentů báze a 1 molekvivalentu kyseliny vinné v ethanolu, t. t. 244 až 250 °C, [a]D 20 = _37,6 °C (c = 0,26, methanol).Normal tartrate is prepared from 2 mol equivalents of base and 1 mol equivalents of tartaric acid in ethanol, mp 244-250 ° C, [α] D 20 = -37.6 ° C (c = 0.26, methanol).
Stejně jako D-6-ethyl-8-ergolin-I-ylacetamid lze připravit tyto další deriváty obecného vzorce I:As well as D-6-ethyl-8-ergolin-1-ylacetamide, the following additional derivatives of formula I can be prepared:
D-6-n-propyl-8-eřgolin-I-ylacetamid, D-6-isopropyl-'8-ergolin-I-ylacetamid, D-6-n-butyl-8-ergolin-I-ylacetamid, D-6-allyl-8-ergolin-I-ylacetamid, D-6-cyklopentyl-8-ergolin-I-ylacetamid, D-6-cyklohexyl-8-ergolin-I-ylacetamid, D-6-diethylamhioethyl-8-ergolin-I-ylacetamid.D-6-n-propyl-8-ergolin-1-ylacetamide, D-6-isopropyl-8-ergolin-1-ylacetamide, D-6-n-butyl-8-ergolin-1-ylacetamide, D-6 -allyl-8-ergolin-1-ylacetamide, D-6-cyclopentyl-8-ergolin-1-ylacetamide, D-6-cyclohexyl-8-ergolin-1-ylacetamide, D-6-diethylamhioethyl-8-ergolin-1 -ylacetamide.
Claims (15)
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS767932A CS195905B1 (en) | 1976-12-06 | 1976-12-06 | 6-substituted derivatives of d-8-ergolin-i-ylacetic acid amide and process for preparing thereof |
| SE7712611A SE7712611L (en) | 1976-12-06 | 1977-11-08 | NEW 6-SUBSTITUTED DERIVATIVES OF D-8-ERGOLINE-I-YLACETAMIDE, SALTS THEREOF AND A PROCEDURE FOR THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING THESE DERIVATIVES |
| FI773498A FI773498A7 (en) | 1976-12-06 | 1977-11-18 | NYA SUBSTITUERADE DERIVAT AV D-8-ERGOLIN-1-YLAETTICCYRAMID DERAS SALTER FOERFARANDE FOER DERAS FRAMSTAELLNING OCH DESSA INNEHAOLLANDE FARMACEUTISKA MEDEL |
| GB48536/77A GB1540787A (en) | 1976-12-06 | 1977-11-22 | 6-substituted d-8-ergolin-i-ylacetamides |
| BE182902A BE861161A (en) | 1976-12-06 | 1977-11-24 | NEW D-8-ERGOLIN-I-YLACETAMIDE DERIVATIVES SUBSTITUTED IN POSITION 6, THEIR SALTS, THEIR PREPARATION PROCESS AND COMPOSITIONS |
| FR7735948A FR2372833B1 (en) | 1976-12-06 | 1977-11-29 | |
| JP14333077A JPS5384995A (en) | 1976-12-06 | 1977-12-01 | 66substituted derivative of dd88ergolineeiiylacetamide salts thereof process for preparing same and medicine containing same |
| AU31160/77A AU510710B2 (en) | 1976-12-06 | 1977-12-02 | 6-substituted derivatives of d 8-ergolin-1-ylacetamide |
| DE19772753880 DE2753880A1 (en) | 1976-12-06 | 1977-12-02 | NEW 6-SUBSTITUTED DERIVATIVES OF D-8-ERGOLIN-I-YLACQUIC ACID AMIDE AND ITS SALTS, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENTS |
| ES464753A ES464753A1 (en) | 1976-12-06 | 1977-12-05 | D-6-allyl-8-ergol-I-ylacetamide |
| AT867977A AT355734B (en) | 1976-12-06 | 1977-12-05 | METHOD FOR PRODUCING NEW 6-SUBSTITUTED DERIVATIVES OF D-8-ERGOLIN-I-YLESSIGOIC ACID AMIDE AND THE SALTS THEREOF |
| CA292,418A CA1065860A (en) | 1976-12-06 | 1977-12-05 | 6-substituted derivatives of d-8-ergolin-1-ylacetamide, their salts, a process for the preparation thereof and composition containing same |
| US05/857,994 US4182883A (en) | 1976-12-06 | 1977-12-06 | D-6-allyl-8-ergol-I-ylacetamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS767932A CS195905B1 (en) | 1976-12-06 | 1976-12-06 | 6-substituted derivatives of d-8-ergolin-i-ylacetic acid amide and process for preparing thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS195905B1 true CS195905B1 (en) | 1980-02-29 |
Family
ID=5429294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS767932A CS195905B1 (en) | 1976-12-06 | 1976-12-06 | 6-substituted derivatives of d-8-ergolin-i-ylacetic acid amide and process for preparing thereof |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4182883A (en) |
| JP (1) | JPS5384995A (en) |
| AT (1) | AT355734B (en) |
| AU (1) | AU510710B2 (en) |
| BE (1) | BE861161A (en) |
| CA (1) | CA1065860A (en) |
| CS (1) | CS195905B1 (en) |
| DE (1) | DE2753880A1 (en) |
| ES (1) | ES464753A1 (en) |
| FI (1) | FI773498A7 (en) |
| FR (1) | FR2372833B1 (en) |
| GB (1) | GB1540787A (en) |
| SE (1) | SE7712611L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU553809B2 (en) * | 1981-07-21 | 1986-07-31 | Farmitalia Carlo Erba S.P.A. | Ergoline derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1439953A (en) * | 1965-01-28 | 1966-05-27 | Sandoz Sa | New ergolene derivatives and their preparation |
| US3966941A (en) * | 1970-09-23 | 1976-06-29 | Spofa United Pharmaceutical Works | Composition for preventing lactation or pregnancy in mammals and the method for using the same |
| US3920664A (en) * | 1972-07-21 | 1975-11-18 | Lilly Co Eli | D-2-halo-6-alkyl-8-substituted ergolines and related compounds |
| NL7400790A (en) * | 1973-02-02 | 1974-08-06 | ||
| CS177530B1 (en) * | 1974-07-19 | 1977-07-29 | Miroslav Semonsky | New nbeta-substituted derivatives of b-beta-aminoethyl-ergoline-i their salts and methods for the production thereof |
| US3959288A (en) * | 1974-12-13 | 1976-05-25 | Eli Lilly And Company | 8-Oxymethylergolines and process therefor |
-
1976
- 1976-12-06 CS CS767932A patent/CS195905B1/en unknown
-
1977
- 1977-11-08 SE SE7712611A patent/SE7712611L/en unknown
- 1977-11-18 FI FI773498A patent/FI773498A7/en not_active Application Discontinuation
- 1977-11-22 GB GB48536/77A patent/GB1540787A/en not_active Expired
- 1977-11-24 BE BE182902A patent/BE861161A/en unknown
- 1977-11-29 FR FR7735948A patent/FR2372833B1/fr not_active Expired
- 1977-12-01 JP JP14333077A patent/JPS5384995A/en active Pending
- 1977-12-02 AU AU31160/77A patent/AU510710B2/en not_active Expired
- 1977-12-02 DE DE19772753880 patent/DE2753880A1/en not_active Withdrawn
- 1977-12-05 CA CA292,418A patent/CA1065860A/en not_active Expired
- 1977-12-05 AT AT867977A patent/AT355734B/en not_active IP Right Cessation
- 1977-12-05 ES ES464753A patent/ES464753A1/en not_active Expired
- 1977-12-06 US US05/857,994 patent/US4182883A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| FR2372833B1 (en) | 1980-05-16 |
| DE2753880A1 (en) | 1978-06-08 |
| GB1540787A (en) | 1979-02-14 |
| CA1065860A (en) | 1979-11-06 |
| FR2372833A1 (en) | 1978-06-30 |
| ATA867977A (en) | 1979-08-15 |
| SE7712611L (en) | 1978-06-07 |
| FI773498A7 (en) | 1978-06-07 |
| US4182883A (en) | 1980-01-08 |
| AU3116077A (en) | 1979-06-07 |
| AU510710B2 (en) | 1980-07-10 |
| ES464753A1 (en) | 1978-09-01 |
| AT355734B (en) | 1980-03-25 |
| BE861161A (en) | 1978-03-16 |
| JPS5384995A (en) | 1978-07-26 |
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